Fibroblast growth factor receptor signaling as therapeutic targets in female reproductive system cancers

Zhu, Dong-Li; Tuo, Xiao-Mei; Rong, Yu; Zhang, Kun; Guo, Yan

doi:10.7150/jca.44727

Cited by 14 publications

(13 citation statements)

References 92 publications

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“…Gain- or loss-of-function mutations of the FGFR family are driving forces of several pathological conditions, highlighting them as targets for pharmaceutical intervention [ 22 ]. In cancer, the FGF/FGFR family regulates cellular proliferation, differentiation, apoptosis, angiogenesis and inflammation through different mechanisms, including aberrant expression, mutation and gene amplification [ 29 , 30 , 31 , 32 ]. The classical FGF signaling can be transduced by RAS/MAPK, PI3K/Akt, Src tyrosine kinase and STAT pathways, which consist targets of current anti-cancer approaches [ 29 , 32 , 33 ].…”

Section: Basic Fibroblast Growth Factor (Bfgf): a Pro-angiogenic Gmentioning

confidence: 99%

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Zahra

Sajib

Mikelis

2021

Cancers

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Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date.

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Section: Basic Fibroblast Growth Factor (Bfgf): a Pro-angiogenic Gmentioning

confidence: 99%

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Zahra

Sajib

Mikelis

2021

Cancers

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“…FGFR signaling is also implicated in ovarian cancer [21]. Unlike in other cancers, overactive FGFR signaling is characterized by overexpression rather than mutation in OvCa and interacts with PI3K/AKT signaling to promote cancer progression.…”

Section: Discussionmentioning

confidence: 99%

“…Given its important role, several multitarget tyrosine kinase inhibitors, ligand traps and monoantibodies that target FGFR signaling have now entered clinical trials of OvCa [21].…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain

Guo

et al. 2021

Aging

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Aim: Overexpression of BCL2L1 (BCL-xL) was associated with platinum resistance in ovarian cancer (OvCa). However, role of copy number (CN) gain of BCL2L1 in OvCa remains elusive. Methods: In silico analyses of multiple public datasets were perform. Validation was carried out in our tissue microarray (TMA) of OvCa cases. In vitro and in vivo assays was performed to explore potential targeted compound against BCL2L1-gained OvCa. Results: BCL2L1 was gained in ~60% of OvCa. BCL2L1 was differentially expressed between healthy and cancerous ovarian cases. BCL2L1 gain was not prognostic either in overall or in progression-free survival but higher BCL2L1 expression was associated with worsened survival, indicating biological distinction between CN gain and overexpression of the gene. BCL2L1 gain was associated with multi-resistance to various drug with no significant sensitivity to any single agent. Only CRISPR-mediated BCL2L1 knockout, but not shRNA could be inhibitive. Combined genetic silencing of FGFR4/NCAM and BCL2L1 with shRNA induced potent inhibition of BCL2L1-gained OvCa with durable effect. Combined inhibition of FGFR/BCL-xL was required for inhibiting BCL2L1-gained OvCa in vitro and in vivo. Only dual inhibition of FGFR/BCL-xL without platinum was tolerable in vivo. Conclusion: Gain of BCL2L1 is associated with resistance to multiple anti-cancer agents in OvCa. Dual inhibition of FGFR4 and BCL-xL showed potent effect and tolerable toxicity, holding promise to further translation.

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“…Therefore, it is not surprising that that such a pleiotropic pathway, when dysregulated, can also contribute to a broad range of pathologies, including cancer [12,13]. Aberrant FGFR signaling has been identified in breast, lung, pancreatic and many gynecological cancers, including endometrial, uterine epithelial adenocarcinoma, ovarian, and cervical [8,[14][15][16][17][18][19][20]. Dysregulation of FGFR signaling can contribute to cancer development and progression in multiple ways.…”

Section: Introductionmentioning

confidence: 99%

FGF signalling facilitates cervical cancer progression

et al. 2022

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Cervical cancer is one of the most frequently diagnosed cancers in women worldwide. While cervical cancer is caused by human papillomavirus (HPV), not all females infected with HPV develop the disease, suggesting that other factors might facilitate its progression. Growing evidence supports the involvement of the fibroblast growth factor receptor (FGFR) axis in several cancers, including gynecological. However, for cervical cancer, the molecular mechanisms that underpin the disease remain poorly understood, including the role of FGFR signaling. The aim of this study was to investigate FGF(R) signaling in cervical cancer through bioinformatic analysis of cell line and patient data and through detailed expression profiling, manipulation of the FGFR axis, and downstream phenotypic analysis in cell lines (HeLa, SiHa, and CaSki). Expression (protein and mRNA) analysis demonstrated that FGFR1b/c, FGFR2b/c, FGFR4, FGF2, FGF4, and FGF7 were expressed in all three lines. Interestingly, FGFR1 and 2 localized to the nucleus, supporting that nuclear FGFRs could act as transcription factors. Importantly, 2D and 3D cell cultures demonstrated that FGFR activation can facilitate cell functions correlated with invasive disease. Collectively, this study supports an association between FGFR signaling and cervical cancer progression, laying the foundations for the development of therapeutic approaches targeting FGFR in this disease.

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Fibroblast growth factor receptor signaling as therapeutic targets in female reproductive system cancers

Cited by 14 publications

References 92 publications

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain

FGF signalling facilitates cervical cancer progression

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